How Do Proteins Leave a Cell? The ER and Golgi Explained

How do proteins get out of a cell, and what do the ER and the Golgi do? Cells in your pancreas make insulin, but insulin works in your blood, and it is far too big to pass through the cell's border. So how does it get out? Follow a protein from the ribosome that builds it, through the ER, the Golgi and a fleet of membrane bubbles, and see how it leaves the cell without ever crossing the border. No biology background needed. This is video 7 of a series that builds up cell biology from scratch. 0:00 Insulin has to get out 0:46 The address label 2:20 The ER, a maze 3:43 Bubbles 4:45 The Golgi, a post office 5:51 Out of the cell 7:29 How we know 8:20 Recap and what's next The fine print (things the video simplifies) The address label is the signal sequence: a stretch of eight or more oily (nonpolar) amino acids at the start of the chain. The helper that grabs it is the signal-recognition particle (six proteins and one RNA). It docks the ribosome at the translocator, a protein channel in the ER membrane, and an enzyme (signal peptidase) cuts the label off. In the video the label leads the chain through the door. In the cell it stays in the door while the rest of the chain loops through. Insulin's precursor finishes part of its entry into the ER just after it is built. Other labels send proteins into the nucleus, mitochondria and other compartments; those proteins are finished first and carried in afterwards. In the ER, helper proteins (chaperones) hold unfolded chains, bridges form between sulfur atoms, and many proteins get their first sugar chain. Misfolded proteins are sent back out through a door and broken down by the proteasome. Cystic fibrosis: the most common mutations make a chloride channel (a door for one of the pieces of salt) that is only slightly misfolded, and the ER keeps it back. A bubble is shaped by a coat of proteins, which falls off before it merges. Other proteins (SNAREs) help the two membranes merge. How proteins move from sac to sac inside the Golgi (in small bubbles, or with the sacs themselves maturing) is not settled. The video draws small bubbles. Insulin is made as proinsulin, one chain: the B chain, a middle part (the C-peptide) and the A chain, joined by two bridges between B and A. The middle part is cut out in the young storage bubbles after they leave the Golgi. "Thousands of bubbles": counts in mouse beta cells are about 10,000. When blood sugar rises, the beta cell's calcium rises, and that triggers the bubbles to merge. The insulin leaves into the fluid around the cell and reaches the blood. The experiment: L. G. Caro and George Palade followed radioactive leucine (one of the twenty beads) through the pancreas cells of guinea pigs that make digestive enzymes, not insulin (published 1964). The experiments that stopped the cells' fuel burning were by J. D. Jamieson and George Palade (1968). Sources OpenStax Biology 2e (free): https://openstax.org/details/books/bi... (sections 4.4, 4.5, 5.4, 15.5, 37.1, 37.3) Alberts et al., Molecular Biology of the Cell, 4th ed. (free on NCBI Bookshelf): "The Endoplasmic Reticulum", "The Compartmentalization of Cells", "The Molecular Mechanisms of Membrane Transport and the Maintenance of Compartmental Diversity", "Transport from the ER through the Golgi Apparatus", "Transport from the Trans Golgi Network to the Cell Exterior: Exocytosis", "Molecular Motors" Caro and Palade, "Protein synthesis, storage, and discharge in the pancreatic exocrine cell. An autoradiographic study", J Cell Biol 20 (1964) Jamieson and Palade, "Intracellular transport of secretory proteins in the pancreatic exocrine cell. IV. Metabolic requirements", J Cell Biol 39 (1968) Liu et al., "Biosynthesis, structure, and folding of the insulin precursor protein", Diabetes Obes Metab 20 (2018) Hou, Min and Pessin, "Insulin granule biogenesis, trafficking and exocytosis", Vitam Horm 80 (2009) The Nobel Prize in Physiology or Medicine 1974 and 1999: https://www.nobelprize.org